Cargo diffusion shortens single-kinesin runs at low viscous drag*

Molecular motors drive active transport in cells. Thermal diffusion of the cargo can impose a randomly directed, fluctuating mechanical load on the motor carrying the cargo. Recent experiments highlighted a strong asymmetry in the sensitivity of kinesin run length to load direction, raising the intriguing possibility that cargo diffusion may non-trivially influence motor run length. To test this possibility, we employed Monte Carlo simulations to evaluate the transport of cargo by a single kinesin. Our simulations included the physiologically relevant viscous drag and interrogated a large parameter space of viscosities, cargo sizes, and motor velocities that captures their respective ranges in live cells. We found that cargo diffusion shortens single-kinesin runs by imposing load in the direction of transport, which more severely impairs kinesin; this load is absent in the diffusion-free case. Viscous drag counters the diffusion-based effect, yielding an unexpected non-monotonic variation in run length. Our findings highlight the importance of cargo diffusion on single motor functions, particularly under physiological conditions.